Differentiation, regulation, and death of T helper cell subsets during infection with Leishmania major.
The development and regulation of specific types of immune responses are dependent on understanding the biology of T helper cell (Th cells) subsets. We primarily use murine infections with the intracellular protozoan parasite, Leishmania major, as our model to investigate Th1/2 cell biology, where following infection, some inbred strains of mice develop a Th1 response and heal, but others develop a Th2 response and fail to control parasite replication. We focus on three major questions: 1. What factors are involved in Th cell development? 2. How can we switch an established immune response from one type to another? 3. How are immune responses downregulated once the parasites are eliminated? We demonstrated that interleukin (IL)12 promotes Th1 cell development and that IL12 is an effective adjuvant for cell-mediated immunity. We are now defining factors regulating the expression of the IL12 receptor and the importance of CD28-B7 interactions for the development of vaccine-induced immunity. We also found that IL12, in combination with chemotherapy, abrogates a Th2 response. These results have implications for treatment of infectious diseases, autoimmunity, and allergy. Currently, we are studying how such switching occurs. Finally, we found that TNFRp55-/- mice are unable to heal leishmanial lesions in spite of eliminating the parasites. This result suggests that the tumor necrosis factor receptor (TNFR) p55 plays a critical, and previously unrecognized, role in downregulating pathogen-induced inflammatory responses. Our current hypothesis is that the TNFRp55 is required for induction of cell death in these lesions, and that in its absence, lymphocytes accumulate at the site of inflammation.
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Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104, USA.
D000818:Animals; D016923:Cell Death / Q000276:immunology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000276:immunology*; D051379:Mice; D016176:T-Lymphocyte Subsets / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000473:pathology